The Smell of Pain

The Smell of Pain

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The Power of Olfaction in the Relief of Pain

Sarah A. LoBisco, ND

According to the American Academy of Pain Management (AAPM), millions of Americans suffer from pain. In fact, chronic pain affects more of the population than diabetes, heart disease, and cancer combined.1 The resultant high cost in management of this condition is not just in dollars ($560-635 billion in 2010), but also in the resultant poor quality of life for those afflicted, due to its ineffective management.1

For example, 50-75% of patients dying of cancer report pain, even though means were implemented to provide relief from their discomfort. Furthermore, after marijuana, prescription drugs for pain control are the second-most abused category of drugs in the United States, and the problem of overdose fatalities continues to rise.1

The emotional turmoil, disruption of daily routines, and the desperation to relieve unrelenting pain could be contributing factors to this high abuse rate of powerful analgesics. Currently, over half of pain sufferers feel hopeless about their condition and 77% report depression. Sixty percent of those in chronic pain experience breakthrough pain that interrupts their day, while 86% of chronic pain patients have sleep problems.1

Mood disturbances such as anxiety, learned helplessness, stress, and insomnia can impede full recovery from any chronic condition. For patients who experience chronic pain, a perpetuating cycle of heightened nociceptive response can result from the combination of their anticipatory and unrelenting discomfort and non-restorative sleep. Therefore, easing emotional stressors, balancing mood, and correcting insomnia are important components in an integrative approach to the management of pain perception and its treatment.2,3

Following a brief review of the physiology behind pain perception, this paper will explore the implications of how the additive effects of therapeutic essential oils with placebo directly affect pain perception and have clinical relevance for both chronic pain sufferers and those with disordered pain processing disorders, such as fibromyalgia.

The Amygdala’s Role in Emotional Modulation of Pain Perception

The amygdala is responsible for interpreting and setting the emotional value of input from the environment. This, in turn, shapes behavior and affective responses, including reactions to potential danger. As nociceptive stimulations can be interpreted as harmful, the amygdala plays a role in conditioned or stress-induced analgesia.

The amygdala consists of 4 main groups of nuclei that include the superficial, basolateral, central, and medial nuclei. The central nucleus of the amygdala (CeA) is the main component of the central group of amygdala nuclei and is the most studied amygdaloid structure for its role in nociception.

The CeA has many associations in various brain structures that assist with its modulation of autonomic function, perception, and nociception.4-9Among these, dopamine, noradrenaline, and serotonin in the brain modulate affective, emotional, and motivational aspects of nociception. Anti-nociception can be induced by neuropeptides such as oxytocin, vasopressin, corticotrophin-releaseing hormone (CRF), and noradrenergic or cholinergic agonists.4

During lasting aversive situations, the CeA may induce hypoalgesia, but not acutely affect nociception. In persistent pain states, such as inflammatory, visceral, or neuropathic pain, a long-lasting functional plasticity of CeA activity can occur. The result is hyperalgesia, aversive behavioral reactions, and affective anxiety-like states.4 All of the above scenarios indicate that the emotional center of our brain modulates adaptive and sensory responses.

Epigenetics & the Smell of Fear and Pain

A controversial rodent study provided evidence that anxiety behavior can be passed down epigenetically through the sense of smell, even for several generations.10 In this experiment, mice were trained to fear the chemical smell of acetophenone by simultaneously being exposed to the scent while receiving small electric shocks. As a result, the rodents learned to associate acetophenone with pain. This was made evident by a shuddering response in the presence of the scent but in the absence of electrical shocks.

An interesting aspect of this study was that despite never being exposed to acetophenone, the offspring of the sensitized male mice exhibited increased sensitivity when introduced to its smell. Furthermore, the third generation and the mice conceived in vitro by these sensitized male mice inherited this same fearful reaction.

The researchers found that the responses in the frightened mice correlated to changes in the brain structures responsible for the processing of odors. Specifically, the acetophenone-sensitized mice and their decedents had a greater number of neurons that produce a receptor protein for this odor, compared with control mice. The receiving structures to the acetophenone-detecting receptors, such as those involved with fear, were also larger.

The proposed mechanism of the trans-generational inheritance was DNA methylation. Specifically, the fearful mice exhibited less methylation markings on the acetophenone-sensing gene in their sperm cells.10

The Role of Environment in Pain Perception

A recent human study supported the role of the environment in gene methylation and resultant pain perception.11 In order to determine methylated regions associated with high or low pain sensitivity (differentially methylated regions, or DMRs, for pain), the authors evaluated genome-wide DNA methylation patterns in 50 identical twins and 50 unrelated individuals, who differed in heat-pain sensitivity.

When assessing for genome-wide variance among monozygotic twins (MZ) and the controls, the researchers found that 106 heterozygous variants had evidence for allele-specific methylation (ASM). This occurred overall in approximately 50% of the sample, and >99% of these variants showed concordance within the MZ twin pairs.

Results revealed that the strongest DMR signal was located on the pain gene TRPA1. Specifically, the presence of a regulatory DNA methylation region in a CpG-island (cytosine-phosphate-guanosine) shore of the TRPA1 promoter affected expression at this region for thermal pain sensitization.11

The ability to inactivate inhibitory descending pain pathways and activate stimulatory pain pathways can help us modulate the mood disorders experienced by those in chronic pain.4Brady and Schneider described how classic fibromyalgia (FM) sufferers have lower levels of central nervous system and total body serotonin, with associated lower pain thresholds.12 For this reason, using medication to strengthen descending inhibitory pathways, such as increasing serotonin or norepinephrine at the supraspinal levels, have been used in FM treatment.4

Although this study will likely help with drug development, it is intriguing for integrative practitioners in that it provides powerful evidence that we can also modulate pain perception through nutritional and environmental epigenomics. The findings can be applied clinically by testing for the need for additional methylation support and resultant neurotransmitter availability via evaluation of methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs), or by providing specific neurotransmitter precursors such as 5-hydroxytryptophan (5HTP) after assessing neurotransmitter levels. Substances such as cinnamaldehyde and camphor have been shown to have bimodal effects on pain relief on mouse TRPA1.13

The fact that emotional stressors can cause dysfunction in limbic and descending antinociceptive systems,4-9,12 alleviation of anxiety and boosting positive expectations could alter pain perception at the level of amygdala. For this reason, there exists an option to modulate the stress response by addressing initial perception, thereby preventing the need to attend to more complicated biochemistry downstream.

The Calming Effect of Essential Oils

Aromatherapy is well-studied for its ability to modulate the stress response. The effects of aroma to quickly induce physical relaxation and decrease the activation of the sympathetic nervous system are important aspects of using essential oils for pain control.14-17

In one study, the effects of aroma massage on sympathetic tone and sleep in middle-aged women with hypertension was evaluated.2 Middle-aged women were selected due to the changes they often experience in the autonomic nervous system, including increases in the adrenal stress hormones. These physiological shifts can lead to increased blood pressure (BP) and psychological effects such as depression, anxiety, and insomnia.

The experiment consisted of an intervention group (n=28) that received the application of the aroma massage and aroma body cream. A massage with a body cream with an artificial fragrance served as placebo (n=28), and the control group (n=27) received no intervention. Subjects had a total of 5 massage sessions within 4 weeks.

The essential oil blend body cream used in the study consisted of lavender, marjoram, ylang-ylang, and neroli, in a ratio of 20:10:15:2, respectively. The oils were diluted to 3% within a carrier oil. Lavender was used for its historic properties to balance the nervous system and its sleep promoting properties. Marjoram was selected for its reported parasympathetic nervous system modulation. For its hypotensive and heart rhythm modulation, ylang-ylang was included. Finally, neroli was added for its effect on sleep and mood. The main chemical constituents of these oils consisted of linalyl acetate (lavender), terpinen-4-ol (marjoram), benzyl acetate (ylang-ylang), and limonene (neroli). The study compared BP measurements at home, in the office, and ambulatory levels.

The results demonstrated a significant and positive effect using an essential oil blend in subjects receiving aromatherapy vs controls, in terms of systolic blood pressure (SBP) and sleep quality. The aroma massage group experienced an approximate reduction of 15 mm Hg for home measurements of SBP, compared to a reduction of 6 mm Hg SBP in the placebo group. In-office SBP measurements in the aroma massage group decreased consistently from 12 mm Hg after the first massage, to 11 mm Hg after the fifth massage. The placebo group did not show a consistent reduction in SBP in-office, from the first to the fifth massage. There was no difference in diastolic blood pressure (DBP) or 24-hour ambulatory BP across groups. Importantly, sleep quality was improved in the intervention group only.2

Limitations of the study included 1) smell preference of participants possibly confounding emotional regulation across groups; and 2) dilution and preparation of the essential oil that incorporated heating the carrier oil, which could interfere with the potency and levels of active constituents.2,12-15

Another study, using a mixture of lavender, Roman chamomile, and neroli, in a 6:2:0.5 ratio, also demonstrated a positive effect on anxiety, sleep, and BP in a group of 56 post-operative patients with ischemic heart disease in the ICU, who had undergone percutaneous coronary intervention (PCI) during coronary angiography.3 Participants were allocated to either the aromatherapy or conventional nursing care (controls).

Subjects in the intervention group received 2 drops of the oil blend inhaled through 10 deep breaths, 10 times prior- and 10 times post-PCI. An aroma stone was also placed under the intervention group’s pillow until the following morning. BP was measured at baseline and 14 times post-treatment.

The results demonstrated a significant difference in outcomes of anxiety and sleep for the intervention group vs the conventional-care PCI group in the ICU. Furthermore, although the SBP and DBP of both groups did not show a significant difference by time or in a group-by-time interaction, a significant difference was observed between groups. Of note, the control group BP increased immediately before and after the PCI procedure; whereas, in the aromatherapy group, BP after aromatherapy treatment before the PCI procedure was approximately 12 mm Hg lower than on admission day, and was maintained at a similar level.3 This provided additional support for the potential of essential oils to negate a stress-induced rise in BP, as noted in the previous study.2

One limitation of this study was that the essential oils were refrigerated. Delicate constituents in the oil can be damaged if the oils’ constituents aren’t properly maintained at optimal temperatures.14-17 The authors also pointed out that various essential oils have been found to have differing effects on BP, displaying the complex biochemistry of essential oils. Therefore, the specific selection of essential oils and the active constituents present is paramount for the desired results.

Odor Analgesia

The effect of odor on analgesia may have several different mechanisms, as determined by a small study.18 This study, consisting of 24 subjects equally divided into 2 groups, tested to what extent placebo effects were behind previous reports of analgesia benefits of essential oils. Twelve subjects were told that a lavender odor would reduce pain (informed), whereas the other 12 subjects were not (not-informed).

Prior to the experiments, the ability of each subject’s odor detection and recognition was evaluated by the T&T olfaction test. The effectiveness of lavender (Lavandula angustifolia) was examined for sleep, anxiety, alleviating pain unpleasantness, and to help the mind and body relax. The subjects received 5 separate electrical stimulations to the forefinger at 100-115% of individual pain threshold, 10 sec apart, to obtain a baseline. The intensity of the painful stimulus and its unpleasantness were then measured. The investigators examined the following: the effectiveness of lavender for sleep, anxiety, alleviation of pain unpleasantness, and helping the mind and body relax. All subjects were administered a lavender-odor or no-odor treatment during application of painful stimulation. Concurrent respiratory recordings were documented. After painful stimulation, the subjects were asked to rate their experience of pain and its unpleasantness on a visual analogue scale, and the results were correlated to breathing patterns.

The researchers concluded that the information given to the subjects regarding a lavender odor, the lavender odor itself, and slower breathing patterns all contributed to reduced perceptions of pain and unpleasantness during painful stimulation. This suggested that placebo did play a role in the aromatherapy benefit of analgesia, and in the following ways:

The sensory process of olfaction affects changes in regions in brain activity through its ascension to various parts of the brain, including the amygdala. The fact that the sense of smell directly links to the limbic region of the brain suggests that smell can quickly modify pain sensation and unpleasantness through its emotional modulation.10,18

Odor stimulation can alter respiratory patterns with odor stimulation. Through inspiration, odor molecules reach the receptors of the olfactory nerve and activate the olfactory limbic areas, which can unconsciously change breathing patterns through stimulation.

The power of placebo effect may be unconsciously engendered by aromatherapy. This may have relevance for which odors to use in aromatherapy.

One of the limitations of this study was the fact that the study did not use pure, therapeutic essential oils. Rather, a lavender odor prepared in ethanol was used for the odor treatment, and no-odorant litmus strips for the no-odor treatments.Although the ethanol odor was said to be left exposed to the air until the smell of alcohol dissipated, it could have affected both pleasantness and biochemical aspects of the essential oil.12-15 Furthermore, the consideration of the nocebo effect wasn’t explored, which might have provided further support for the power of suggestion in pain relief.

The Role of Expectation in Pain Relief

Evidence-based medicine is based on the assumption that the placebo effect has an effect on an outcome of a trial; therefore, the intervention must show superiority to this “power of the mind” in order to be deemed “effective.” For pain studies this is especially relevant, due to the role that emotions and expectations play in perception.

It is thought that the effectiveness of placebo depends on a subject’s expectations of outcome. In a study published in the February, 2013, issue of Neuroimage, effects of the participants’ expectations of a strong vs weak placebo effect against control were evaluated.19 (Strength of placebo was established by informing subjects of different price levels for the placebo treatments.) Functional magnetic resonance imaging (fMRI) was used to measure differences in pain perception in regions of the brain. Overall, the placebo effects were associated with brain activation in regions of pain perception. For pain anticipation and administration, placebo-related responses in the rostral anterior cingulate cortex( rAcc) were consistent across subjects; however, the rAcc responses were higher for the strong vs weak placebo.19

In another study, this time evaluating the efficacy of acupuncture, the powerful effect of placebo on 99 patients with chronic fatigue syndrome was significant with regards to physical and mental fatigue.20 This well-controlled placebo trial compared sham acupuncture in a control group (CG) to an experimental group (EG). Treatment comprised a total of 8 sessions (30 min each) over a period of 4 consecutive weeks. The CG followed exactly the same treatment schedule as the EG and was delivered by the same TCM practitioner; controls receiving sham acupuncture were made to believe they were receiving standard acupuncture. Specially-designed needles were used that were applied in such a way that the same acupuncture points were pricked but not penetrated.

Both the CG and EG groups experienced significant improvements in physical and mental fatigue across the course of the experiment, demonstrating the effect of placebo. However, the EG group demonstrated comparatively large effect sizes. It was concluded that acupuncture was powerful beyond placebo; however, as noted, the results may have been confounded by the placebo bias expectation of the treatment.20

The “Program in Placebo Studies and Therapeutic Encounter”21 was established to decipher the mysteries of the placebo effect and the therapeutic encounter, including the roles of expectation and experience. In a trial that was part of this new experimental series within Beth Israel Deaconess Medical Center and another Boston hospital, the efficacy of the placebo effect for pain relief was evaluated using migraine sufferers.21-29

This particular study included 66 subjects who collectively suffered over 450 migraine attacks.23 The migraines were classified as throbbing headaches commonly accompanied by nausea, vomiting, and sensitivity to light and sound. Patients documented their pain 30 minutes after the onset of a migraine, which served as a baseline. For 6 subsequent migraine attacks, participants randomly received 2 envelopes with placebo or rizatriptan (a triptan drug commonly used for migraines). The envelopes were labeled with the drug name (positive expectation condition), or with “placebo” (negative expectation condition), or as containing the drug “or placebo” (neutral condition). The subjects then documented their pain at baseline and at 2 ½ hours after treatment.

Rizatriptan was found superior to placebo for pain relief; however, the efficacy of the drug-labeled placebo and of the drug itself were similar. Furthermore, it was found that both the placebo and drug effect increased with an expectation of effect by participants. Specifically, the greatest effect was found progressively from conditions labeled as (a) placebo, (b) drug or placebo, to (c) drug.22-24 The authors concluded, “Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect.”23

The mechanism behind the role of expectancy and efficacy of the placebo effect has been examined with regards to the role of dopamine, a powerful pleasure neurotransmitter involved in reward, motivation, and motor function. Using a model of subjects with Parkinson disease, findings have indicated that dopamine release in the nigrostriatal and mesolimbic pathways could be modulated with expectation of therapeutic benefit of an intervention.

Studies have demonstrated that dopamine release in regions of the striatum were correlated to open administration of active medication.30 Dorsal striatum dopamine release was highly determined by medication experience in response to placebo. Furthermore, the addition of expectation of clinical improvement accounted for dopamine release in an additional region of the brain, the ventral striatum.

In other words, when given an intervention expected to contain 75% or higher active medication versus the expectation of a lower-efficacy medication, dopamine release was highest. The implication for the practitioner is in the fact that expectation and uncertainty play roles in modulating clinical responses of the placebo effect.30,31

Biochemical Modulation of Pain with Essential Oils

Combing the effect of expectation by inhaling a calming scent and the resultant limbic modulation of olfaction, the use of essential oils could bridge the therapeutic benefit of an intervention with our knowledge about the power of placebo for pain relief. In fact, the effects of essential oils beyond placebo have well been documented.2,3,18,32-37

In a randomized, blinded, placebo-controlled trial, the positive effect of aromatherapy abdominal massage on dysmenorrhea in 95 female nursing students was demonstrated.32 The intervention consisted of applying essential oils once daily for 7 days prior to menstruation. The aromatherapy intervention (n=48) consisted of essential oils of cinnamon, clove, rose, and lavender (in a ratio of 1.5:1.5:1:1), which were applied in a base of almond oil. The placebo group (n=47) received only almond oil in their massage oil. The 2 groups switched interventions for a second phase of the trial. Duration of pain and bleeding were significantly decreased compared to baseline measures in the aromatherapy group, and no side effects were reported.

This study supported 2 mechanisms for the pain relief induced by essential oils, including their modulation of limbic system and the biochemical properties of the oils themselves. Clove was thought to improve circulation, while lavender’s effects were attributed to analgesia, sedation, and anticonvulsant effects. Cinnamon’s effects were considered anti-inflammatory, via its reported inhibition of PGE2 production, as well as its modulation of estrogen activity. Finally, rose was considered supportive in the regulation of the menstrual cycle and its effects on the uterus.

Limitations of this study include failure to control proportions of constituents of the oils or therapeutic effects based on chemotypes. There is also still a paucity of studies supporting the use of essential oils to reduce excessive menstrual bleeding.32

In another small randomized, crossover-designed study with 26 participants, pre- and post-treatment quantitative sensory ratings of contact heat, pressure, and ischemic pain were compared across 3 separate inhalation aroma treatment conditions.33 These 3 conditions consisted of the essential oil of lavender, the essential oil of rosemary, or distilled water (control). Changes in pain intensity and unpleasantness during treatment were subjectively reported for each condition using a visual analog scale. Subjects’ autonomic response was also measured, using salivary cortisol.

There were no differences in quantitative pain ratings between conditions; however, global impression of pain intensity and unpleasantness was reduced in the essential oil intervention group, compared with the control group.

This study had several limitations in determining the effect of the essential oil alone, and the placebo or nocebo effect. For instance, the participants were not blinded to the interventions for pain perception. Furthermore, they were selected based on their participation in a past experiment with aromatherapy for pain. As perception of pain from the past experiment could influence expectation, this factor could have had an effect on both cortisol levels and pain intensity. Another limitation of this study was that standardization of the essential oils via dosages, chemotype, and constituents were not mentioned in this study.33 Notwithstanding these limitations, the fact that essential oils were demonstrated to have an effect on central processing of pain is evidence of their potency in combination with the placebo effect.

A small study (n=17) of college women in their 20s investigated the effects of plant fragrance on emotional symptoms and biochemical effects occurring in the premenstrual phase of their cycles.34 The severity of premenstrual symptoms was determined based on a menstrual distress questionnaire over at least 2 menstrual cycles. None of the subjects had severe premenstrual syndrome or premenstrual dysphoric disorder.

All subjects underwent physical examination and interviews, and systemic disorders were ruled out. An olfactory function test on all subjects was administered prior to the study. Autonomic activity was assessed using heart rate variability (HRV), and the Profile of Mood States (POMS) questionnaire was used to measure pain perception. The participants were administered a lavender oil aroma treatment (intervention) or water (control) treatment during the late-luteal phase of their cycles.

The results favored the lavender inhalation group, reflected by an increase in parasympathetic activity within 10 minutes of exposure and lasting for at least 25 minutes following the initial inhalation. Lavender inhalation also produced a decrease in 2 POMS subscales – depression/dejection and confusion (common premenstrual symptoms) – lasting as long as 35 minutes after the aroma stimulation. Finally, improved sleep was reported in those subjects in the intervention group,34 a vital component of healing from pain.

Lavender’s pharmacological action was considered a key factor, including its modulation of cyclic adenosine monophosphate (cAMP), associated with sedation. One of lavender’s constituents, linalool, is also thought to have sedative effects due to its inhibition of glutamate binding.34 All of these mechanisms are important for pain relief.

Limitations in this study were the small sample size, mild PMS classification, and the potential of placebo effect due to the distinctly different aromas of lavender vs water.

Various other studies have provided additional support for the pharmacological efficacy of essential oils for pain, partly via their anti-inflammatory effects.36-38 Harvard Medical School has also reported on several studies showing peppermint oil to be beneficial to patients suffering from irritable bowel pain.38 Beyond decreasing inflammation, a proposed mechanism is the blocking of calcium channels by methanol in peppermint, thereby relaxing the smooth muscles of the intestinal wall.

Conclusion

As integrative practitioners, we can never ignore the cause of pain. We must always dig deeper to find the trigger, whether it be structural, biological, traumatic, or emotional. Furthermore, the important role of expectation, stress physiology, and belief in the intervention are all important to consider for pain control and could prevent the need for more extensive downstream biochemical modulation. Due to the fact that trauma and fear could be epigenetic factors that predispose one to pain, we must not ignore the addition of nutritional and lifestyle interventions to modulate environmental imprinting in our patients.

Sarah LoBisco, ND, is a graduate of the University of Bridgeport College of Naturopathic Medicine (UBCNM). She is licensed in Vermont as a naturopathic doctor and holds a BA in psychology. Dr LoBisco is a professional speaker on integrative medical topics, has several journal publications, and is a candidate for post-doctoral certification in functional medicine. Dr LoBisco currently has a private integrative medical consulting practice located in Ballston Spa, NY, where she integrates her training in holistic medical practices with conventional medicine. Her recent blogs and information on her clinic can be found at www.dr-lobisco.com andwww.saratoga.com/living-well. She is also a featured expert blogger on Dr Oz’s sharecare.com.

Knox R. Half Of A Drug’s Power Comes From Thinking It Will Work. NPR Web site. http://www.npr.org/blogs/health/2014/01/10/261406721/half-a-drugs-power-comes-from-thinking-it-will-work?ft=1&f=1027. Accessed January 10, 2014.

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